Oncolytic herpes simplex virus vector therapy of breast cancer in C3(1)/SV40 T-antigen transgenic mice
Oncolytic herpes simplex virus vector therapy of breast cancer in C3(1)/SV40 T-antigen transgenic mice
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DOI：
10.1158/0008-5472.can-04-3353
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发表时间：
2005-02-15
期刊：
影响因子：
11.2
通讯作者：
Rabkin, SD
中科院分区：
文献类型：
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作者：
Liu, RB;Varghese, S;Rabkin, SD
溶瘤单纯疱疹病毒载体是一种有前途的癌症治疗策略，作为直接的细胞毒性剂，诱导抗肿瘤免疫反应，并作为抗癌基因的表达。进展依赖于代表性的临床前模型来评估治疗。在本研究中，使用C3（1）/T-Ag转基因小鼠模型，检查了已经在临床试验中的两个溶瘤单纯疱疹病毒载体家族（G207和NV 1020系列）用于治疗乳腺癌。雌性小鼠自发发生乳腺癌，C3（1）/T-Ag衍生的肿瘤细胞系M6 c形成可植入肿瘤。在体外和体内，通过缺失ICP 47和US 11启动子而衍生自G207的G47 Delta比G207更有效。然而，通过缺失ICP 47和插入LacZ而衍生自NV 1020的NV 1023在体外对M6 c细胞的细胞毒性与G47 Delta一样，它不抑制S.c. M6 c肿瘤，但延长了脑内肿瘤荷瘤小鼠的生存期。相反，表达白细胞介素12的NV 1042、NV 1023抑制s.c. M6 c肿瘤生长的程度与G47 Delta相似，但在脑内肿瘤中不如NV 1023有效。在自发产生的乳腺肿瘤模型中，当仅治疗每只小鼠的第一个产生的肿瘤时，G47 Delta抑制肿瘤子集的生长，并且当治疗所有肿瘤时，G47 Delta显著延迟肿瘤进展。当治疗第一个乳腺肿瘤并去除剩余的乳腺时，NV 1042在抑制注射肿瘤的生长和进展方面比G47 Delta更有效。
Oncolytic herpes simplex virus vectors are a promising strategy for cancer therapy, as direct cytotoxic agents, inducers of antitumor immune responses, and as expressers of anticancer genes. Progress is dependent upon representative preclinical models to evaluate therapy. In this study, two families of oncolytic herpes simplex virus vectors (G207 and NV1020 series) that have been in clinical trials were examined for the treatment of breast cancer, using the C3(1)/T-Ag transgenic mouse model. Female mice spontaneously develop mammary carcinomas, and the C3(1)/T-Ag-derived tumor cell line M6c forms implantable tumors. Both in vitro and in vivo, G47Delta, derived from G207 by deletion of ICP47 and the US11 promoter, was more efficacious than G207. Whereas NV1023, derived from NV1020 by deletion of ICP47 and insertion of LacZ, was as cytotoxic to M6c cells in vitro as G47Delta, it did not inhibit the growth of s.c. M6c tumors but did extend the survival of intracerebral tumor bearing mice. In contrast, NV1042, NV1023 expressing interleukin 12, inhibited s.c. M6c tumor growth to a similar extent as G47Delta, but was less effective than NV1023 in intracerebral tumors. In the spontaneously arising mammary tumor model, when only the first arising tumor per mouse was treated, G47Delta inhibited the growth of a subset of tumors, and when all tumors were treated, G47Delta significantly delayed tumor progression. When the first mammary tumor was treated and the remaining mammary glands removed, NV1042 was more efficacious than G47Delta at inhibiting the growth and progression of injected tumors.